Reactivation of Mitogen-activated Protein Kinase (MAPK) Pathway by FGF Receptor 3 (FGFR3)/Ras Mediates Resistance to Vemurafenib in Human B-RAF V600E Mutant Melanoma

Yadav, Vipin; Zhang, Xiaoyi; Liu, Jiangang; Estrem, Shawn T.; Li, Shuyu; Gong, Xueqian; Buchanan, Sean G.; Henry, James R.; Starling, James J.; Peng, Sheng-Bin

doi:10.1074/jbc.m112.377218

Cited by 175 publications

(151 citation statements)

References 36 publications

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“…Other reports have also suggested that FGFR3 activation mediates resistance to cetuximab in wild-type squamous tumor cells with KRAS mutations and to vemurafenib in BRAF V600E melanoma cells ( 62,63 ).…”

Section: Fgf and Drug Resistancementioning

confidence: 99%

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

et al. 2013

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The fi broblast growth factor/fi broblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifi cations, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, classspecifi c toxicity profi les and correctly designing clinical trials to address these different issues.Signifi cance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov;3(3);

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Section: Fgf and Drug Resistancementioning

confidence: 99%

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

et al. 2013

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“…A375R1, A375R3, M14R, and SH4R cells were generated by treating their respective parental cells with gradually increasing concentrations of vemurafenib, up to 2 mmol/L as described previously (10). The resistant mechanism of A375R1, A375R3, and M14R cells was associated with RTK/RAS activation and MAPK reactivation (10).…”

Section: Development Of Vemurafenib-resistant Cell Linesmentioning

confidence: 99%

“…A375R1, A375R3, M14R, and SH4R models with acquired resistance to vemurafenib were generated by treating respective parental cells with gradually increasing concentrations of vemurafenib, up to 2 mmol/L, as previously described (10). A375R2 cells were generated by treating A375 cells with a high concentration of vemurafenib (2 mmol/L) for 1 week, followed by culturing with vemurafenib (1 mmol/L) for up to 20 passages.…”

Section: Generation Of Vemurafenib-resistant Cell Linesmentioning

confidence: 99%

“…Alternatively, activation of MAPKredundant pathways such as PI3K/Akt as a consequence of PTEN loss (17) or overexpression of RTKs such as PDGFRb and IGF1R have also been reported to induce resistance in B-RAF V600E melanoma (7,18,19). In addition, secretion of growth factors such as HGF or FGF has also been implicated in resistance to B-RAF inhibition (10,11,20,21). Although the resistant mechanisms are frequently associated with MAPK reactivation, treatment with the MEK inhibitor trametinib, or with trametinib plus dabrafenib, has not been very effective in patients 1 Oncology Discovery Research, Lilly Research Laboratories, Indianapolis, Indiana.…”

Section: Introductionmentioning

confidence: 99%

“…The most common resistant mechanism is MAPK pathway reactivation, which is caused by genetic mutation of MEK or different Ras isoforms (7)(8)(9), upstream activation of receptor tyrosine kinases (RTK) such as FGFR3 and c-Met (10,11), expression of B-RAF V600E splice variants that dimerize in presence of the B-RAF inhibitor (12), amplification of B-RAF (13,14), and upregulation of MAP3Ks such as COT or C-RAF (15,16). Alternatively, activation of MAPKredundant pathways such as PI3K/Akt as a consequence of PTEN loss (17) or overexpression of RTKs such as PDGFRb and IGF1R have also been reported to induce resistance in B-RAF V600E melanoma (7,18,19).…”

Section: Introductionmentioning

confidence: 99%

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The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation

Yadav

Burke

Huber

et al. 2014

Molecular Cancer Therapeutics

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114

117

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B-RAF selective inhibitors, including vemurafenib, were recently developed as effective therapies for melanoma patients with B-RAF V600E mutation. However, most patients treated with vemurafenib eventually develop resistance largely due to reactivation of MAPK signaling. Inhibitors of MAPK signaling, including MEK1/2 inhibitor trametinib, failed to show significant clinical benefit in patients with acquired resistance to vemurafenib. Here, we describe that cell lines with acquired resistance to vemurafenib show reactivation of MAPK signaling and upregulation of cyclin D1 and are sensitive to inhibition of LY2835219, a selective inhibitor of cyclin-dependent kinase (CDK) 4/6. LY2835219 was demonstrated to inhibit growth of melanoma A375 tumor xenografts and delay tumor recurrence in combination with vemurafenib. Furthermore, we developed an in vivo vemurafenib-resistant model by continuous administration of vemurafenib in A375 xenografts. Consistently, we found that MAPK is reactivated and cyclin D1 is elevated in vemurafenib-resistant tumors, as well as in the resistant cell lines derived from these tumors. Importantly, LY2835219 exhibited tumor growth regression in a vemurafenib-resistant model. Mechanistic analysis revealed that LY2835219 induced apoptotic cell death in a concentration-dependent manner in vemurafenib-resistant cells whereas it primarily mediated cell-cycle G 1 arrest in the parental cells. Similarly, RNAi-mediated knockdown of cyclin D1 induced significantly higher rate of apoptosis in the resistant cells than in parental cells, suggesting that elevated cyclin D1 activity is important for the survival of vemurafenib-resistant cells. Altogether, we propose that targeting cyclin D1-CDK4/6 signaling by LY2835219 is an effective strategy to overcome MAPK-mediated resistance to B-RAF inhibitors in B-RAF V600E melanoma.

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Reduced FRG1 expression promotes angiogenesis via activation of the FGF2‐mediated ERK/AKT pathway

et al. 2023

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Identifying novel targets that control both tumorigenesis and angiogenesis can aid in developing a more potent anti‐angiogenic therapeutic strategy. We previously reported that reduction of FRG1 is associated with increased p38‐MAPK signaling in prostate cancer and with elevated MEK–ERK signaling in breast cancer. Here, we reveal the role of FRG1 in tumor angiogenesis. Our findings demonstrate that depleted FRG1 levels enhance the proliferation, migration, and tubule formation of HUVECs in a paracrine manner, and this was further substantiated in multiple animal models. Mechanistically, FRG1 depletion activated the expression of FGF2 in breast cancer cells, which triggered the ERK/AKT cascade in endothelial cells. As FRG1 affects multiple tumorigenic properties and it is upstream of FGF2, it can be explored as a therapeutic target that is less prone to resistance.

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Reactivation of Mitogen-activated Protein Kinase (MAPK) Pathway by FGF Receptor 3 (FGFR3)/Ras Mediates Resistance to Vemurafenib in Human B-RAF V600E Mutant Melanoma

Cited by 175 publications

References 36 publications

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation

Reduced FRG1 expression promotes angiogenesis via activation of the FGF2‐mediated ERK/AKT pathway

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